Alcohol and stimulant substance abuse disorders have a devastating economic and societal impact on the United States population. Alcohol and stimulant substance dependency is a multi-factorial neurological disease. The use of such drugs impacts an array of neurotransmission circuits in the brain, with a suggested final common pathway of activation of the mesolimbic reward circuit that is mediated via enhanced dopamine release. Over time, repeated exposure to these drugs causes modification of the neurotransmission circuits and adaptations in post-receptor signaling cascades. The effects of this neuronal modification are twofold. First, a reduction in the ability of natural rewards to activate the reward pathways leads to depressed motivation and mood, and increased compulsion to take more drugs. Second, there is a production of long-lasting memories related to the drug experience that, when stimulated by stressful events or exposure to drug-associated or mood-associated cues, act to stimulate cravings for the drug.
For many individuals, an innate neurochemical anomaly renders them susceptible to substance dependency or addictive behavior, even before any long-term effects of alcohol on neurological processing are evident. It is clear, however, that excessive drinking over time can lead to the impairment of brain function and result in structural brain changes in frontal and prefrontal areas of the brain, which are associated with cognition. Impaired cognition and judgment can therefore become permanent.
Alcohol affects the mesolimbic dopamine circuit by modifying the activity of two key receptors in the dopamine circuit, the GABAA receptor and NMDA receptor. GABA (gamma-aminobutryic acid) is a neurotransmitter that is a predominant inhibitory transmitter in areas of the brain such as the cortex and basal ganglia. The NMDA (N-methyl-D-aspartate) receptor is a ligand-gated ionic channel activated by and involved in the release of the neurotransmitter glutamate, which is an important excitatory transmitter in the brain. The positive affect on the mesolimbic dopamine circuit creates a self-reinforcing cycle of neuropathophysiological reward that drives individuals to become alcohol dependent. Alcohol increases chloride channel ion flow, relative to the post-synaptic chloride channel at rest, by engaging a GABAA receptor site. Benzodiazepines have a similar affect.
Acute exposure to alcohol results in the up regulation of NMDA and down regulation of the GABA-ergic system. Repeated exposure results in cross-tolerance and cross-dependence between alcohol and benzodiazepines. Consequently, an alcohol dependent person experiences stress, a down regulation of GABAA and an increase in the severity of withdrawal symptoms when he or she attempts to withdraw.
Therefore, when an alcoholic attempts to initiate abstinence or stop consuming alcohol, he or she may experience withdrawal symptoms, including cravings, which often result in a failure to stop consuming alcohol. Traditional alcohol withdrawal symptoms include anxiety, tremors, difficulty sleeping, elevated pulse and blood pressure, nausea, and vomiting. In some cases, withdrawal symptoms may be more severe and result in complications, including seizures, hallucinosis, hallucinations with severe tremors (or “delirium tremens”, DTs) and difficulty regulating body temperature. These complications may often be fatal. In an exemplary case, withdrawal symptoms begin appearing 6 to 12 hours after a prior consumption of alcohol. Alcohol withdrawal syndrome may occur 6 to 48 hours after a prior consumption of alcohol.
Psychostimulants are a class of central nervous system stimulants and include cocaine, crack cocaine, ephedrine, amphetamines, such as dextroamphetamine (commonly referred to as amphetamine), methamphetamine, and phenmetrazine, methylenodioxyamphetamine (MDA), and methylenodioxymethamphetamine (MDMA or “ecstasy”), and analogs thereof. Amphetamine-like drugs are classified as indirect action agonists of noradrenergic, dopaminergic, and serotonergic synapses which result from inhibiting both neurotransmitters reuptake and the enzyme monoamine oxidase (MAO). They are competitive inhibitors of noradrenaline and dopamine transport and, in high doses, also inhibit serotonin reuptake. They cause non-calcium dependent dopamine and noradrenaline release.
Stimulants affect a number of neurological circuits, including dopaminergic, beta-adrenergic, serotonergic, glutamatergic, GABAergic circuits, and ultimately results in impaired dopamine function. GABAA functionality is eventually impaired.
At lower doses, stimulants result in a feeling of euphoria, an increase in energy, a decrease in fatigue, and an increase in mental acuity. As dosing increases, a person starts to experience tremors, emotional instability, restlessness, irritability, and feelings of paranoia and panic. At higher doses, a person experiences intense anxiety, paranoia, hallucinations, hypertension, tachycardia, hyperthermia, respiratory depression, heart failure, and seizures.
Traditional withdrawal symptoms for those trying to end their abuse of psychostimulants include: depressed mood, fatigue, vivid and unpleasant dreams, difficulty sleeping or excessive sleeping, increased appetite, anxiety, and agitation. Cravings for the psychostimulant are particularly pronounced and may recur for many months, if not years. A return of “normal” mood and the ability to experience pleasure may take a significant amount of time due to the depletion or modification of neurotransmitters.
Alcohol and psychostimulant substance abuse are often associated with changes in food selection and intake that lead to calorie and protein malnutrition and disruption of energy expenditure. The resulting malnutrition is related to deficient food intake, malabsorption, increased protein turnover, liver disease, intensity of drug addiction, anorexia, and poor food and drink consumption. Furthermore, the disturbance of social and familial links can itself result in poor nutrition. Malnutrition, in turn, is associated with impairment of immune function. Therefore, restoration and maintenance of normal physiological function can be regarded as an important objective when treating substance dependencies. Effective treatment of alcohol substance abuse should address the neurological, nutritional, and psychosocial disturbances that both cause and exacerbate the abuse.
The customary treatment of alcohol dependency includes the administration of vitamin B and C complexes, benzodiazepines (to calm agitation and blunt withdrawal symptoms), and, sometimes, disulfuram (to prevent alcohol use). The traditional medical detoxifications involve replacing alcohol with substances pharmacologically similar to alcohol in order to reduce withdrawal agitation. Detoxification can take 3-5 days, involves sedation with potentially dependence forming drugs, and is generally uncomfortable for the patient.
Traditional treatments for managing withdrawal and craving for alcohol and/or psychostimulants (such as cocaine) may include the administration of benzodiazepines (e.g. lorezepam) if agitation or anxiety is present, antidepressants to treat persistent depression and dopamine-agonists to increase brain dopamine. These treatments, however, have limited success and have high dropout rates. Dropout can refer to several different types of treatment events related to the premature cessation of treatment, including times when patients dropout during treatment and when patients relapse following treatment.
A review of the various pharmacological treatments existing for the treatment of alcohol dependency can be found in A Practice Guideline for the Treatment of Patients With Substance Use Disorders Alcohol, Cocaine and Opioids, produced by the Work Group on Substance Use Disorders of the American Psychiatric Association and published in Am. J. Psychiatry 152:11, November 1995 Supplement. An updated review of the treatment of alcohol dependency was created by Mayo-Smith et al., JAMA Jul. 9, 1997, Vol. 278, No. 2, who conclude by indicating that the benzodiazepines (alprazolam, diazepam, halazepam, lorazepam or oxazepam) are agents suitable for the treatment of alcohol dependency, whereas beta-blockers (propranolol), neuroleptics (chlorpromazine and promazine), clonidine and carbamazepine, may be used in coadjuvant therapy, but their use is not recommended as a monotherapy. A benzodiazepine is any of a group of chemically similar psychotropic drugs with potent hypnotic and sedative action, used predominantly as anti-anxiety (anxiolytic) and sleep-inducing drugs. Side effects of these drugs may include impairment of psychomotor performance; amnesia; euphoria; dependence; and rebound (i.e., the return of symptoms) transiently worse than before treatment, upon discontinuation of the drug.
In certain conventional uses, flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. In conventional doses, flumazenil [ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a][1,4]benzodiazepine-3-carboxylate] therefore acts as a benzodiazepine antagonist which selectively blocks the effects exerted on the central nervous system via the benzodiazepine receptors. This active principle is indicated to neutralize the central sedative effect of the benzodiazepines; consequently, it is conventionally used in anesthesia to end the general anesthesia induced and maintained with benzodiazepines in hospitalized patients, or to stop the sedation produced with benzodiazepines in patients undergoing brief diagnostic or therapeutic procedures on an inpatient or outpatient basis.
Some clinical studies have examined the role of flumazenil in the reversal of alcohol withdrawal syndrome. Gerra et al., 1991, Current Therapeutic Research, Vol. 50, 1, pp 62-66, describe the administration to 11 selected alcoholics (who did not have cirrhosis, metabolic disorders, convulsions, addictions to other substances or psychiatric disorders) of 2 mg/day of flumazenil divided into 4 doses (0.5 mg), intravenously (IV) via a continuous drip, in saline solution, every 6 hours for 48 hours. The use of 0.5 mg of flumazenil is based on the presentation of pharmaceutical preparations that contain said active principle but not on studies performed in humans concerning the level of occupation of the receptors involved. The flumazenil was administered at the rate of 0.5 mg of flumazenil every 6 hours (i.e., 0.08 mg/hour of flumazenil). The tests performed by Gerra et al. present some characteristics that are far from the actual circumstances, for example, the tests were performed on a small sample (11 individuals) of select patients not representative of the pathology considered since it is relatively customary that these patients may have cirrhosis, metabolic disorders, addictions to other substances (cocaine, heroin, etc.) and/or psychiatric disorders. Moreover, Gerra et al. do not present data concerning the evaluation of dependency or craving either before or after administration of the drug. Most importantly, however, Gerra et al. discloses the administration of very small quantities of flumazenil over long periods of time, which was not particularly effective at treating alcohol dependency.
Nutt et al. [Alcohol & Alcoholism, 1993, Suppl. 2, pp 337-341. Pergamon Press Ltd.; Neuropschychopharmacology, 1994, Vol. 10, 35, part 1, Suppl., p. 85f) describe the administration to 8 alcoholics in the acute withdrawal phase of 2 mg of flumazenil, by IV, for 1 minute. The results obtained after the administration of flumazenil were not completely satisfactory since in some cases, there was an immediate worsening of the withdrawal symptoms, especially of sweats and anxiety. In other cases, the withdrawal symptoms disappeared but returned a few hours later. Since flumazenil is metabolized and eliminated very rapidly, the IV administration of a relatively high dose of flumazenil in a single dose of 2 mg, for 1 minute, has several disadvantages since such dosing triggers undesired side effects, and the bulk of flumazenil administered yields no pharmacological response and results in unnecessary expense.
Moreover, the results obtained by Gerra et al. and by Nutt et al. are not conclusive since in some cases, no significant changes were observed in either the blood pressure or the heart rate of patients after the administration of flumazenil, an immediate worsening of the withdrawal symptoms was observed, especially sweats and anxiety, and the tests were performed using a very small non-representative patient sample.
In two articles by Sheryl S. Moy (Skipper Bowles Center for Alcohol Studies, Department of Psychiatry and UNC Neuroscience Center), investigators disclose the use of flumazenil to block anxiety created by ethanol withdrawal in rats. According to Moy et al. (2000), in rat models of the ethanol withdrawal syndrome, flumazenil can reverse anxiogenic withdrawal effects such as inhibition during a social interaction test (File et al. 1989, 1992) and reduced open arm exploration on an elevated plus maze (Moy et al. 1997) Further in Moy et al. (2000) and Uzbay et al. (1995) it was reported that flumazenil could prevent the agitation and stereotyped behavior induced by withdrawal from long-term ethanol exposure in rats. Doses, however, were provided for rat models and cannot be readily translated to human dosage levels. Moreover, the prior art teaches the use of flumazenil in a conventional benzodiazepine treatment model, which requires the substitution of ethanol usage with large quantities of benzodiazepine to alleviate withdrawal symptoms.
However, all disclosed uses of flumazenil in the treatment of alcohol withdrawal and addiction have relied on either the single administration of large quantities of flumazenil or on-going administrations of very low quantities of flumazenil over long periods of time. Moreover, the disclosed administrative regimens has not applied the use of flumazenil, or a class of compounds represented by flumazenil, for treating psychostimulant substance abuse at all. Furthermore, conventional treatments for alcohol and/or psychostimulant dependency have had limited success and often have undesirable side effects. New approaches are needed that can improve treatment outcomes and reduce the risk of relapse. Thus, an improved treatment methodology for treating alcohol and/or psychostimulant substance abuse is desirable.
In addition, conventional treatments for controlling withdrawal symptoms and cravings for alcohol and/or psychostimulants have had limited success and often have undesirable side effects. Thus, an improved treatment methodology for controlling cravings and withdrawal symptoms caused by alcohol and/or psychostimulant substance abuse would be desirable.
It would also be desirable to have an improved methodology and protocol for treating alcohol and/or psychostimulant substance abuse, which results in reduced patient dropout rates.